Hypoxia of the growing liver accelerates regeneration

Erik Schadde; Christopher Tsatsaris; Marzena Swiderska-Syn; Stefan Breitenstein; Martin Urner; Roman Schimmer; Christa Booy; Birgit Roth Z'graggen; Roland H Wenger; Donat R Spahn; Martin Hertl; Stuart Knechtle; Ann Mae Diehl; Martin Schläpfer; Beatrice Beck-Schimmer

doi:10.1016/j.surg.2016.05.018

Hypoxia of the growing liver accelerates regeneration

Surgery. 2017 Mar;161(3):666-679. doi: 10.1016/j.surg.2016.05.018. Epub 2016 Jul 16.

Authors

Affiliations

¹ Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Division of Transplant Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL; Department of Surgery, Cantonal Hospital Winterthur, Zürich, Switzerland. Electronic address: erik.schadde@uzh.ch.
² Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
³ Division of Hepatology, Department of Gastroenterology, Duke University, Durham, NC.
⁴ Department of Surgery, Cantonal Hospital Winterthur, Zürich, Switzerland.
⁵ Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland.
⁶ Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland.
⁷ Division of Transplant Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL.
⁸ Division of Transplantation, Department of Surgery, Duke University, Durham, NC.
⁹ Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland; Department of Anesthesiology, University of Illinois Chicago, Chicago, IL.

PMID: 27436690
DOI: 10.1016/j.surg.2016.05.018

Abstract

Background: After portal vein ligation of 1 side of the liver, the other side regenerates at a slow rate. This slow growth may be accelerated to rapid growth by adding a transection between the 2 sides, i.e., performing portal vein ligation and parenchymal transection. We found that in patients undergoing portal vein ligation and parenchymal transection, portal vein hyperflow in the regenerating liver causes a significant reduction of arterial flow due to the hepatic arterial buffer response. We postulated that the reduction of arterial flow induces hypoxia in the regenerating liver and used a rat model to assess hypoxia and its impact on kinetic growth.

Methods: A rat model of rapid (portal vein ligation and parenchymal transection) and slow regeneration (portal vein ligation) was established. Portal vein flow and pressure data were collected. Liver regeneration was assessed in rats using computed tomography, proliferation with Ki-67, and hypoxia with pimonidazole and HIF-1α staining.

Results: The rat model confirmed acceleration of regeneration in portal vein ligation and parenchymal transection as well as the portal vein hyperflow seen in patients. Additionally, tissue hypoxia was observed after portal vein ligation and parenchymal transection, while little hypoxia staining was detected after portal vein ligation. To determine if hypoxia is a consequence or an inciting stimulus of rapid liver regeneration, we used a prolyl-hydroxylase blocker to activate hypoxia signaling pathways in the slow model. This clearly accelerated slow to rapid liver regeneration. Inversely, abrogation of hypoxia led to a blunting of rapid growth to slow growth. The topical application of prolyl-hydroxylase inhibitors on livers in rats induced spontaneous areas of regeneration.

Conclusion: This study shows that pharmacologically induced hypoxic signaling accelerates liver regeneration similar to portal vein ligation and parenchymal transection. Hypoxia is likely an accelerator of liver regeneration. Also, prolyl-hydroxylase inhibitors may be used to enhance liver regeneration pharmaceutically.

MeSH terms

Animals
Cell Hypoxia / physiology
Hepatectomy
Ligation
Liver / blood supply*
Liver / pathology*
Liver Regeneration / physiology*
Male
Models, Animal
Portal Vein*
Rats
Rats, Wistar

Grants and funding

R01 DK077794/DK/NIDDK NIH HHS/United States